Fetal growth restriction, or low birthweight is a strong determinant for eventual obesity and Type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulate fetal birthweight and the metabolic health trajectory of the offspring. In the current study, we used genetic model with loss of placental mTOR function (mTORKOPlacenta) to test the direct role of mTOR signaling on birthweight and the metabolic health in the adult offspring. mTORKOPlacenta animals displayed reduced placental area and total weight, as well as fetal bodyweight at embryonic day (e) 17.5. Birthweight and serum insulin levels were reduced; however, β-cell mass was normal in mTORKOPlacenta newborns. Adult mTORKOPlacenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared to littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from a diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.
Brian Akhaphong, Daniel C. Baumann, Megan Beetch, Amber D. Lockridge, Seokwon Jo, Alicia Wong, Tate Zemanovic, Ramkumar Mohan, Danica L. Fondevilla, Michelle Sia, Maria R.B. Pineda-Cortel, Emilyn U. Alejandro
Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β-cell function. One of the mechanisms results from β-cell KATP channel dysfunction (e.g., KCNJ11 (MODY13) or ABCC8 (MODY12) mutations); however, no other β-cell channelopathies have been identified in MODY. We identified a previously unreported non-synonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and β-cell-restricted K+ channel transcript and encodes the two-pore-domain K+ channel TALK-1. Whole-cell K+ currents demonstrated a large gain-of-function with TALK-1 Leu114Pro vs. WT, due to greater single channel activity. Glucose-stimulated membrane potential depolarization and Ca2+ influx was inhibited in mouse islets expressing TALK-1 Leu114Pro (area under the Ca2+ curve [AUC] at 20mM glucose: Leu114Pro 60.1 vs. WT 89.1; P=0.030) with less endoplasmic reticulum Ca2+ storage (cyclopiazonic acid-induced release AUC: Leu114Pro 17.5 vs. WT 46.8; P=0.008). TALK-1 Leu114Pro significantly blunted glucose-stimulated insulin secretion compared to TALK-1 WT in mouse (52% decrease, P=0.039) and human (38% decrease, P=0.019) islets. These data suggest KCNK16 is a previously unreported gene for MODY.
Sarah M. Graff, Stephanie R. Johnson, Paul J. Leo, Prasanna K. Dadi, Matthew T. Dickerson, Arya Y. Nakhe, Aideen M. McInerney-Leo, Mhairi Marshall, Karolina E. Zaborska, Charles M. Schaub, Matthew A. Brown, David A. Jacobson, Emma L. Duncan
BACKGROUND We aimed to determine whether metabolic syndrome (MetS) affects longitudinal trajectories of diabetic complications, including neuropathy, cardiovascular autonomic neuropathy (CAN), and kidney disease in American Indians with type 2 diabetes.METHODS We performed a prospective study where participants underwent annual metabolic phenotyping and outcome measurements. The updated National Cholesterol Education Program criteria were used to define MetS and its individual components, using BMI instead of waist circumference. Neuropathy was defined using the Michigan Neuropathy Screening Instrument index, CAN with the expiration/inspiration ratio, and kidney disease with glomerular filtration rate. Mixed-effects models were used to evaluate associations between MetS and these outcomes.RESULTS We enrolled 141 participants: 73.1% female, a mean (±SD) age of 49.8 (12.3), and a diabetes duration of 19.6 years (9.7 years) who were followed for a mean of 3.1 years (1.7 years). MetS components were stable during follow-up except for declining obesity and cholesterol. Neuropathy (point estimate [PE]: 0.30, 95% CI: 0.24, 0.35) and kidney disease (PE: –14.2, 95% CI: –16.8, –11.4) worsened over time, but CAN did not (PE: –0.002, 95% CI: –0.006, 0.002). We found a significant interaction between the number of MetS components and time for neuropathy (PE: 0.05, 95% CI: 0.01–0.10) but not CAN (PE: –0.003, 95% CI: –0.007, 0.001) or kidney disease (PE: –0.69, 95% CI: –3.16, 1.76). Systolic blood pressure (SBP, unit = 10 mmHg) was associated with each complication: neuropathy (PE: 0.23, 95% CI: 0.07, 0.39), CAN (PE: –0.02, 95% CI: –0.03, –0.02), and kidney disease (PE: –10.2, 95% CI: –15.4, –5.1).CONCLUSION In participants with longstanding diabetes, neuropathy and kidney disease worsened during follow-up, despite stable to improving MetS components, suggesting that early metabolic intervention is necessary to prevent complications in such patients. Additionally, the number of MetS components was associated with an increased rate of neuropathy progression, and SBP was associated with each complication.FUNDING The following are funding sources: NIH T32NS0007222, NIH R24DK082841, NIH R21NS102924, NIH R01DK115687, the Intramural Program of the NIDDK, the NeuroNetwork for Emerging Therapies, the Robert and Katherine Jacobs Environmental Health Initiative, the Robert E. Nederlander Sr. Program for Alzheimer’s Research, and the Sinai Medical Staff Foundation.TRIAL REGISTRATION ClinicalTrials.gov, NCT00340678.
Evan L. Reynolds, Gulcin Akinci, Mousumi Banerjee, Helen C. Looker, Adam Patterson, Robert G. Nelson, Eva L. Feldman, Brian C. Callaghan
GWAS have shown that the common R325W variant of SLC30A8 (ZnT8) increases the risk of type 2 diabetes (T2D). However, ZnT8 haploinsufficiency is protective against T2D in humans, counterintuitive to earlier work in humans and mouse models. Therefore, whether decreasing ZnT8 activity is beneficial or detrimental to β cell function, especially under conditions of metabolic stress, remains unknown. In order to examine whether the existence of human islet amyloid polypeptide (hIAPP), a coresident of the insulin granule, affects the role of ZnT8 in regulating β cell function, hIAPP-expressing transgenics were generated with reduced ZnT8 (ZnT8B+/– hIAPP) or null ZnT8 (ZnT8B–/– hIAPP) expression specifically in β cells. We showed that ZnT8B–/– hIAPP mice on a high-fat diet had intensified amyloid deposition and further impaired glucose tolerance and insulin secretion compared with control, ZnT8B–/–, and hIAPP mice. This can in part be attributed to impaired glucose sensing and islet cell synchronicity. Importantly, ZnT8B+/– hIAPP mice were also glucose intolerant and had reduced insulin secretion and increased amyloid aggregation compared with controls. These data suggest that loss of or reduced ZnT8 activity in β cells heightened the toxicity induced by hIAPP, leading to impaired β cell function and glucose homeostasis associated with metabolic stress.
Jie Xu, Nadeeja Wijesekara, Romario Regeenes, Dana Al Rijjal, Anthony L. Piro, Youchen Song, Anne Wu, Alpana Bhattacharjee, Ying Liu, Lucy Marzban, Jonathan V. Rocheleau, Paul E. Fraser, Feihan F. Dai, Cheng Hu, Michael B. Wheeler
Background: Dietary sodium intake mismatches urinary sodium excretion over prolonged periods. Our aims were to localize and quantify electrostatically bound sodium within human skin using triple quantum filtered (TQF) protocols for magnetic resonance imaging (MRI) and spectroscopy (MRS), and explore dermal sodium in Type 2 Diabetes Mellitus (T2D). Methods: We recruited adult participants with T2D (n=9) and euglycemic participants with no history of Diabetes Mellitus (n=8). All had undergone lower limb amputations or abdominal skin reduction surgery for clinical purposes. We used 20μm in-plane resolution 1H MRI to visualise anatomical skin regions ex vivo from skin biopsies taken intra-operatively, 23Na TQF MRI/MRS to explore distribution and quantification of freely dissolved and bound sodium and Inductively Coupled Plasma Mass Spectrometry to quantify sodium in selected skin samples. Results: Human dermis has a preponderance (>90%) of bound sodium that co-localizes with the glycosaminoglycan (GAG) scaffold. Bound and free sodium have similar anatomical locations. T2D associates with a severely reduced dermal bound sodium capacity. Conclusion: We provide the first evidence for high levels of bound sodium within human dermis, co-locating to the GAG scaffold, consistent with a dermal ‘third space repository’ for sodium. T2D associates with diminished dermal electrostatic binding capacity for sodium.
Petra Hanson, Christopher J. Philp, Harpal S. Randeva, Sean James, J Paul O'Hare, Thomas Meersmann, Galina E. Pavlovskaya, Thomas M. Barber
BACKGROUND. Continued androgen receptor (AR) signaling constitutes a key target for treatment in metastatic castration-resistant prostate cancer (CRPC). Studies have identified 11-ketotestosterone (11KT) as a potent AR agonist, but it is unknown if 11KT is present at physiologically-relevant concentrations in CRPC patients to drive AR activation. The goal of this study was to investigate the circulating steroid metabolome including all active androgens in CRPC patients. METHODS. Metastatic CRPC patients (n=29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multi-steroid profiling employing liquid chromatography-tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing. RESULTS. 11KT was the most abundant circulating active androgen in 97% of CRPC patients (median 0.39 nmol/L, range: 0.03–2.39 nmol/L), constituting 60% (IQR 43-79%) of the total active androgen (TA) pool. Treatment with glucocorticoids reduced 11KT by 84% (49-89%) and testosterone (T) by 68% (38-79%). Circulating TA concentrations at baseline were associated with a distinct intratumoral gene expression signature comprising AR-regulated genes. CONCLUSIONS. The potent AR agonist 11KT is the predominant circulating active androgen in CRPC patients and, therefore, one of the potential drivers of AR activation in CRPC. Assessment of androgen status should be extended to include 11KT, as current clinical approaches likely underestimate androgen abundance in CRPC patients. Trial registrationNetherlands TRIAL REGISTRATION. NL5625(NTR5732) FUNDING. Daniel den Hoed foundation (Hofland) and Wellcome Trust (Investigator Award WT209492/Z/17/Z, Arlt)
Gido Snaterse, Lisanne F. van Dessel, Job van Riet, Angela E. Taylor, Michelle van der Vlugt-Daane, Paul Hamberg, Ronald de Wit, Jenny A. Visser, Wiebke Arlt, Martijn P. Lolkema, Johannes Hofland
White adipose tissue not only serves as a reservoir for energy storage but also secretes a variety of hormonal signals and modulates systemic metabolism. A substantial amount of adipose tissue develops in early postnatal life, providing exceptional access to the formation of this important tissue. Although a number of factors have been identified that can modulate the differentiation of progenitor cells into mature adipocytes in cell-autonomous assays, it remains unclear which are connected to physiological extracellular inputs and are most relevant to tissue formation in vivo. Here, we elucidate that mature adipocytes themselves signal to adipose depot–resident progenitor cells to direct depot formation in early postnatal life and gate adipogenesis when the tissue matures. Our studies revealed that as the adipose depot matures, a signal generated in mature adipocytes is produced, converges on progenitor cells to regulate the cytoskeletal protein MYH9, and attenuates the rate of adipogenesis in vivo.
Sin Ying Cheung, Mohd Sayeed, Krishnamurthy Nakuluri, Liang Li, Brian J. Feldman
Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from bi-allelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from the ER, eliminating its secretion and triggering ER stress. Nevertheless, untreated patients somehow continue to synthesize sufficient thyroxine to yield measurable serum levels that sustain life. We demonstrate that TGW2346R/ W2346R humans, TGcog/cog mice, and TGrdw/rdw rats exhibit no detectable ER export of thyroglobulin, accompanied by severe thyroidal ER stress and thyroid cell death. Nevertheless, thyroxine is synthesized and brief treatment of TGrdw/rdw rats with anti-thyroid drug is lethal to the animals. When untreated, remarkably, thyroxine is synthesized on the mutant thyroglobulin protein, delivered via dead thyrocytes that decompose within the follicle lumen, where they are iodinated and cannabilized by surrounding live thyrocytes. As long as the animals grow a goiter, circulating thyroxine increases. However, when TGrdw/rdw rats age, they cannot sustain goiter growth that provides the dying cells needed for ongoing thyroxine synthesis, resulting in profound hypothyroidism. These results establish a disease mechanism wherein dead thyrocytes support organismal survival.
Xiaohan Zhang, Aaron P. Kellogg, Cintia E. Citterio, Hao Zhang, Dennis Larkin, Yoshiaki Morishita, Hector M. Targovnik, Viviana A. Balbi, Peter Arvan
Bariatric surgery is the most effective method for weight loss in morbid obesity. There is significant individual variability in the weight loss outcomes, yet factors leading to postoperative weight loss or weight regain remain elusive. Alterations in the µ-opioid receptor (MOR) and dopamine D2 receptor (D2R) systems are associated with obesity and appetite control, and the magnitude of initial brain receptor system perturbation may predict long-term surgical weight loss outcomes. We tested this hypothesis by studying 19 morbidly obese women (mean BMI 40) scheduled to undergo bariatric surgery. We measured their preoperative MOR and D2R availabilities using positron emission tomography (PET) with [11C]carfentanil and [11C]raclopride, respectively, and then assessed their weight development association with regional MOR and D2R availabilities at 24-month follow-up. MOR availability in the amygdala consistently predicted weight development throughout the follow-up period, but no associations were found for D2R. This is the first study to demonstrate that neuroreceptor markers prior to bariatric surgery are associated with the postoperative weight loss. Postoperative weight regain may derive from dysfunction in the opioid system, and weight loss outcomes after bariatric surgery may be partially predicted based on preoperative brain receptor availability opening up new potential for treatment possibilities.
Henry K. Karlsson, Lauri Tuominen, Semi Helin, Paulina Salminen, Pirjo Nuutila, Lauri Nummenmaa
Perilipin 2 (PLIN2) is the lipid droplet (LD) protein in β cells that increases under nutritional stress. Down-regulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was down-regulated in mouse β cells, INS1 cells, and human islet cells. β cell specific deletion of PLIN2 in mice on a high fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Down-regulation of PLIN2 in INS1 cells blunted GSIS after 24 h incubation with 0.2 mM palmitic acids. Down-regulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Down-regulation of PLIN2 decreased specific OXPHOS proteins in all three models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2 deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in β cells have an important role in preserving insulin secretion, β cell metabolism, and mitochondrial function under nutritional stress.
Akansha Mishra, Siming Liu, Joseph Promes, Mikako Harata, William I. Sivitz, Brian D. Fink, Gourav Bhardwaj, Brian T. O'Neill, Chen Kang, Rajan Sah, Stefan Strack, Samuel B. Stephens, Timothy H. King, Laura Jackson, Andrew S. Greenberg, Frederick Anokye-Danso, Rexford S. Ahima, James A. Ankrum, Yumi Imai
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